Posaconazole (CAS Registry Number 171228-49-2; CAS Name: 2,5-anhydro-1,3,4-trideoxy-2-C-(2,4-difluorophenyl)-4-[[4-[4-[4-[(1S,2 S)-1-ethyl-2-hydroxypropyl]-1,5-dihydro-5-oxo-4H-1,2,4-triazol-4-yl]phenyl]-1-piperazinyl]phenoxy]methyl]-1-(1H-1,2,4-triazol-1-yl)-D-threo-pentitol) is a triazole antifungal drug represented by the structure:

Posaconazole is used, for example, to prevent and/or treat invasive fungal infections caused by Candida species, Mucor species, Aspergillus species, Fusarium species, or Coccidioides species in immunocompromised patients and/or in patients where the disease is refractory to other antifungal agents such as amphothericin B, fluconazole, or itraconazole, and/or in patients who do not tolerate these antifungal agents.
Currently known processes for the preparation involve a two-step procedure with harsh reaction conditions which necessitate very stable protecting groups, reducing the yield and quality of the triazolone product.
A process of the prior art for the preparation of a triazolone compound is disclosed in WO 96/33178. In this reaction, the triazolone ring in posaconazole is formed by heating of an aromatic carbamate, prepared from the corresponding amine and phenyl chloroformate, and an O-protected hydrazide for 24-48 hours at more than 100° C. Such harsh reaction conditions during condensation of the triazolone ring are believed to cause significant degradation, becoming evident by the darkening of the product which is obtained in a yield of 80% after deprotection. When applied to the synthesis of tetrahydrofuran azole antifungal agents, cleavage of the O-protecting group, typically benzyl, is believed not to be quantitative. Therefore, traces of the protected compound may be found in the respective pharmaceutical composition containing the product. Further, the activation of the aromatic amine as phenyl carbamate involves the mutagenic compound phenyl chloroformate
and substantial amounts of toxic phenol are produced. The prolonged heating of 24 to 48 hours further reduces yield and quality of the product and obviously requires a significant and undue amount of energy.
Another process for the preparation of disubstituted triazolone compounds in general is disclosed in WO 93/09114. Document WO 95/17407 specifically relates to the preparation of posaconazole. Both documents teach the reaction of an aromatic carbamate, prepared as described above, with hydrazine followed by heating with formamide acetate to give an N-substituted triazolone. Said triazolone is alkylated satisfactorily with aliphatic hydrocarbon chains, but not with O-substituted alkyl groups as required for the preparation of posaconazole. As to the use of O-alkylating agents, the process taught by these documents involves a large excess of alkylating agent and thus gives rise to a mixture of N-alkylated and O-alkylated isomers. Consequently, tedious purification is necessary which is costly, time-consuming and reducing the yield for this step to 50% or less, thus rendering the process highly disadvantageous, in particular for industrial-scale processes for the preparation of these triazolone compounds such as posaconazole.
Yet another process is described in WO 2006/007540. A similar reaction is published by Huang et al., Organic Letters 2004, 6 (25) 4795-4798. This reaction involves the activation of an aliphatic amine with phosgene and the addition of unsubstituted formyl hydrazine followed by heating in hexamethyldisilazane at 140° C. for up to 30 hours to give N-unsubstituted triazolone compounds in low to moderate yields. This process has not been described for the synthesis of triazolone-containing antifungal compounds such as posaconazole which would require the reaction with aromatic amines. In this respect, the N-alkylation step following the formation of the triazolone would obviously face the same difficulties and restrictions as described in the context of the prior art documents above.
Summarized, it is noted that all known processes for the synthesis of triazolone compounds, in particular posaconazole, from aromatic amines, such as Y3—NH2 wherein Y3 is an optionally substituted aryl residue, in particular from aromatic amines of formula
require and produce a large amount of toxic and/or polluting reagents, involve prolonged reaction times at high temperatures and, concerning the preparation of posaconazole, are only specifically taught for the benzyl-protected hydrazide

Unprotected or, for example, silyl-protected hydrazides result in complex mixtures with minor contents of posaconazole. For the synthesis of antifungal triazolone compounds, these process constraints cause considerable pollution and waste of materials and/or energy, decrease the quality of the product and leave traces of protected triazolone compounds, in particular benzyl-protected triazolone compounds, especially
in the antifungal agent products and the respective pharmaceutical composition.
Therefore, it was an object of the present invention to provide a novel process which overcomes at least one of the problems of the prior art processes.